1. Field of the Invention
This invention pertains to neurodegenerative diseases and other conditions characterized by neuronal death and/or dysfunction in the central nervous system. The invention also concerns growth factors that are capable of promoting the survival of neurons in the central nervous system. The invention relates specifically to methods of treating neurodegenerative diseases and conditions characterized by neuronal death and/or dysfunction in the central nervous system with the local administration of growth factors.
2. Description of Related Art
Growth factors are natural proteins that play important roles in the nervous system. They are found within nervous tissue as well as in many innervated target tissues. Growth factors promote the growth, survival, and phenotypic differentiation of neurons and/or glial cells. Growth factors also play a role in the remodeling of synaptic connections in the mature nervous system, a process referred to generally as neuronal plasticity. Because of these physiological roles, growth factors are useful for treating central nervous system (CNS) disorders in which the survival and/or proper function of neurons is compromised. Such CNS disorders may arise by many different means, including: (1) physical injury, which causes the degeneration of the axonal processes and/or nerve cell bodies near the site of injury, (2) temporary or permanent cessation of blood flow (ischemia) to parts of the nervous system, as in stroke, (3) intentional or accidental exposure to neurotoxins, such as the cancer and AIDS chemotherapeutic agents cisplatinum and dideoxycytidine (ddC), respectively, (4) chronic metabolic diseases, such as diabetes or renal dysfunction, or (5) neurodegenerative diseases such as Parkinson's disease, Huntington's Disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis (ALS), which result from the degeneration of specific neuronal populations.
The therapeutic effect of a growth factor delivered to the CNS may derive from multiple mechanisms of action. Growth factors may contribute to therapeutic efficacy by promoting the survival and/or maintaining the phenotypic differentiation of a neuronal population that is compromised in a CNS disorder. Additionally, growth factors may act on secondary neuronal populations which are not compromised in a particular CNS disorder but are able to effect beneficial compensatory changes in the CNS in response to growth factor, for example, through neuronal plasticity. In order for a particular growth factor to be potentially useful in treating a CNS disorder, the neuronal population compromised in the CNS disorder or a compensating secondary neuronal population must be responsive to the particular factor. Responsiveness to a particular growth factor is conferred by its cognate growth factor receptor, the vast majority of which belong to the family of receptor tyrosine kinases.
Nerve growth factor (NGF) is the founding member of a defined family of growth factors, called the neurotrophins, that includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, and NT-6. These neurotrophins are known to act via the family of trk tyrosine kinase receptors, i.e., trkA, trkB, trkC, and the low affinity p75 receptor.
Glial cell line-derived neurotrophic factor (GDNF) is a glycosylated disulfide-bonded homodimer that has its closest structural homology to the transforming growth factor (TGF) superfamily of proteins. GDNF was identified and purified using assays based upon its efficacy in promoting the survival and stimulating the transmitter phenotype of mesencephalic dopaminergic neurons in vitro. In vivo, treatment with exogenous GDNF stimulates the dopaminergic phenotype of substantia nigra neurons, and restores functional deficits induced by axotomy or dopaminergic neurotoxins in animal models of Parkinson's disease. Although originally thought to be relatively specific for dopaminergic neurons, subsequent experiments showed that GDNF has neurotrophic efficacy on brain stem and spinal cord cholinergic neurons, both in vitro and in vivo.
GDNF, and the related ligands neurturin, artemin, and persephin, maintain several neuronal populations in the CNS, including midbrain dopamine neurons and motoneurons. The GDNF family of ligands bind to specific GDNF family receptor alpha proteins, which form receptor complexes and signal through the RET receptor tyrosine kinase. GDNF is also capable of signaling directly through alpha receptor, as well as through the neural cell adhesion molecule (NCAM) via activation of Fyn and FAK.
In the CNS, the expression of trkA, the receptor for NGF, is almost exclusively limited to the cholinergic neurons in the basal forebrain. These cholinergic neurons are of particular neurologic interest, because cholinergic neuronal degeneration and/or dystrophy is a hallmark of Alzheimer's disease. The basal forebrain cholinergic neurons can be readily identified in morphologic preparations using acetylcholinesterase histochemistry or with immunohistochemistry using antibody to choline acetyltransferase (ChAT), the synthetic enzyme for acetylcholine, or to p75.
Alzheimer's disease is a progressive dementia characterized by failure of recent memory, amnesia, disturbances in emotional behavior, and difficulty in managing spatial relationships or motor skills. The disease occurs throughout the world and accounts for one-half to two-thirds of all cases of late-life intellectual failure in many developed countries having populations with high life expectancies.
Alzheimer's disease is diagnosed mainly by clinical symptoms, after other causes of dementia have been excluded. After death, the diagnosis can be conclusively established by the observation of numerous characteristic neurofibrillary tangles and senile plaques in the brain that accompany the degeneration seen in Alzheimer's disease.
Progressive region-specific loss and degeneration of selected cells in the association and memory areas of the cerebral cortex is seen in Alzheimer's disease, along with abnormalities in certain subcortical nuclei. Neuronal loss affects especially the large pyramidal cells of the parietal and frontal association areas, the hippocampus and amygdala. Strongly affected hippocampal inputs are those from the entorhinal cortex, cholinergic neurons of the basal forebrain, and noradrenergic neurons of the locus coeruleus. The basal forebrain nucleus of Meynert, from which the major cholinergic projection to the cortex arises, also suffers severe degeneration.
Substantial evidence points to a significant role for basal forebrain cholinergic neurons in the behavioral alterations seen in Alzheimer's patients. The loss of cholinergic function is one of the earliest changes in the disease. The extent of the cholinergic deficit correlates with the degree of memory impairment, and enhancement of cholinergic function by acetylcholinesterase inhibitors produces modest but significant amelioration of symptoms. In animals, lesions of the cholinergic neurons innervating the hippocampus and cortex result in pronounced memory and cognitive deficits that are reversed by drugs that enhance cholinergic function.
Projection neurons producing other monoamine transmitters (norepinephrine, serotonin, and dopamine) and cortical neurons producing glutamate, gamma-aminobutyric acid (GABA), somatostatin, neuropeptide Y, corticotropin releasing factor, substance P and other neuromodulators are also affected in Alzheimer's disease.
While early research pointed to the promise of NGF as a therapeutic for Alzheimer's disease and other neuropathologies, untenable side effects have been observed in human clinical trials using NGF. Systemic administration of NGF at low doses for the treatment of peripheral neuropathy has caused severe muscle pain in some patients, while Alzheimer's patients treated with intracerebroventricular infusions of NGF experienced peripheral rostral muscle pain similar to that reported with peripheral NGF administration, and significant weight loss.
Clinical trials using GDNF for the treatment of Parkinson's disease have also been reported and have shown mixed results. Parkinson's disease is a disorder in which slow degeneration of dopamine-producing neurons, mostly in the nigrostriatal pathway, results in neurological effect. Intraventricular administration of GDNF did not lead to a determinable clinical benefit, and multiple adverse side effects were reported. Local delivery of GDNF to the striatum has also been used to treat Parkinson's disease. Two clinical trials involving the continuous infusion and diffusion of GDNF into the dorsal putamen reported different results, potentially owing at least in part to differences in dosage and delivery.
Importantly, neutralizing anti-GDNF antibodies were detected in sera from several human patients, and in a toxicology study, segmental cerebellar injury characterized by Purkinje and granule cell loss was observed in monkeys receiving GDNF infusion.
Clinical studies involving neurotrophin infusion into the brain parenchyma of patients with neurodegenerative disease have used continuous infusion and relied on diffusion for infusate to reach target tissues. There are a number of difficulties associated with diffusion-based delivery, the most critical being low tissue distribution volume. Without means for monitoring the distribution of infused neurotrophin, it is difficult to determine the therapeutic efficacy. For example, Gill et al. reported in Nat. Med. 9:5899-595, 2003 that, when glial cell line-derived neurotrophic factor (GDNF) was used in clinical studies as a treatment for Parkinson's disease, it was not clear how far GDNF would diffuse away from the catheter tip and that it is possible more rostral portions of the putamen would continue to degenerate if not reached by diffusion. They also found that, as the dose of GDNF was escalated, a high T2 MRI signal intensity was observed around the tip of the catheter, possibly owing to vasogenic edema or protein buildup, which required dosage reduction and potentially further compromised rostral portions of the putamen.
There continues to exist a need for methods and therapeutic compositions useful for the treatment of CNS disorders, including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.